Nonthrombogenic plastic surfaces and preparation thereof

ABSTRACT

A plastic polymer surface rendered substantially nonthrombogenic by heparin chemically combined with quaternary ammonium groups which are chemically bonded to the plastic polymer surface, which is preferably flexible or elastomeric; also several methods of producing same.

United States Patent Inventors Robert I. Leininger;

Richard D. Falb, both of Columbus, Ohio 570,41 1

Aug. 5, 1966 Nov. 2, 197 l The United States of America as representedby the Secretary of the Department of Health Education and Welfare Appl.No. Filed Patented Assignee NONTHROMBOGENIC PLASTIC SURFACES AND 138.8B, 138.8 C, 138.8 D, 138.8 E, 138.8 F, 138.8 U, 138.8 UF,47, 118, 93.1;128/DlG. 22; 3/DIG. 3; 167/74; 424/28, 183

References Cited OTHER REFERENCES Scott, J. E., The Reaction ofLong-Chain Quaternary Ammonium Salts with Acidic Polysaccharides,Chemistry and lndustry,No. 7, Feb. 12, 1955, pp. 168- 169,TP l S 63.

Gott et al., Techniques of Applying a Graphite-Benzalkonium-l-leparinCoating to Various Plastics and Metals," Transactions American Societyfor Artificial Internal Organs, Vol. X, June 25, 1964, pp. 213- 217 Falbet al. Development of Blood-Compatible Polymeric Materials, 29 June1965, Battelle Memorial lnst., pp. l- 19 Published 3 March 1966 PrimaryExaminer-William D. Martin Assistant Examiner-David Cohen Attorney-J. Y.Houghton ABSTRACT: A plastic polymer surface rendered substantiallynonthrombogenic by heparin chemically combined with quaternary ammoniumgroups which are chemically bonded to the plastic polymer surface, whichis preferably flexible or elastomeric; also several methods ofproducingsame.

NONTHROMBOGENIC PLASTIC SURFACES AND PREPARATION THEREOF to a rigidplastic surface by coating the rigid surface with graphite and thentreating the graphite with first zephiran and then heparin. This system,described by Dr. Vincent Gott, inter alia, is not applicable to eitherflexible or elastomeric materials, the use of which is desirable inconnection with artificial lung machines and for other purposesinvolving circulation of blood in contact with the plastic surface. Forthese reasons the graphite system has limited utility.

An important object 'of the present invention is to provide a system ofrendering a plastic surface nonthrombogenic which is applicable toflexible or elastomeric plastics as well as to rigid plastics.

A further object is to provide a polymer surface rendered substantiallynonthrombogenic by heparin chemically bonded to the polymer surface.

Other objects and advantages of the invention will be apparent from thefollowing description and examples of preferred embodiments and speciesthereof.

The invention resides in the new and useful combinations hereindisclosed and is more particularly pointed out in the appended claims.

ln its general aspects the invention provides a plastic polymer surfacerendered substantially nonthrombogenic by heparin chemically combinedwith quaternary ammonium groups which are chemically bonded to theplastic polymer surface. The plastic polymer may be a rigid polymer suchas polystyrene, but preferably is a flexible plastic or elastomericpolymer, since the latter are especially useful in apparatus andequipment to be used in contact with blood. in accordance with theinvention, the plastic polymer surface is rendered substantiallynonthrombogenic by a process which comprises two steps: (a) providingthe said surface with quaternary ammonium groups chemically bonded tothe polymer, and (b) heparinizing the said quaternary ammonium groups.

The polymer surface may be provided with quaternary ammonium groups,step (a), in any suitable way, preferably by chemical treatment afterformation of the polymer surface. For example:

In a first embodiment of step (a) the polymer is provided withchloromethyl groups on its surface which are aminated with a tertiaryamine to fonn the quaternary ammonium groups chemically bonded to thesurface of the polymer.

In a first preferred species of this embodiment, the polymer providedwith chloromethyl groups on its surface is formed by surfacechloromethylation of a polymer having a reactive hydrogen on an aromaticring, e.g. polystyrene, styrene-butadiene polymer, a polyphenyleneoxide, or the like, and the resulting chloromethylated surface isaminated immediately without drying with a tertiary amine, e.g. triethylamine, dimethyl aniline, or pyridine.

In a variation of this first preferred embodiment, the surfacing withchloromethyl groups is applied to polystyrene grafted to anotherpolymer. Particular species of this embodiment may employ polyethylene,polypropylene, ethylene-propylene rubber, silicone rubber, ortetrafiuoro-ethylene polymer, radiation grafted with polystyrene as thepolymer to be chloromethylated, and then aminated with the tertiaryamine.

In a second species of this first preferred embodiment, the surfacingwith chloromethyl groups is applied to a polymer having surface hydroxylgroups by reaction with chloroacetic anhydride and is followed withamination by the tertiary amine.

in other species of this first preferred embodiment a polymer such as apolyolefin or a silicone rubber containing methyl groups may besubjected to surface chlorination to form the surface-chloromethylatedpolymer which may then be treated with tertiary amine, etc.

In a second embodiment of step (a) the polymer is provided with tertiaryamine groups on its surface, which are quaternized by reaction with aquatemizing reagent, e.g. methyl iodide or benzyl chloride, to form thequaternary ammonium groups chemically bonded to the surface of thepolymer.

In a first preferred species of this embodiment the polymer providedwith tertiary amine groups on-its surface is formed by radiationgrafting of a tertiary amine, e.g. Z-Vinylpyridine or 4- vinylpyridine,or the like, to the surface of the polymer to be heparinized, e.g.polystyrene, polyethylene, silicone rubber, tetrafiuoroethylene polymer,,a natural rubber, a synthetic elastomer, or other radiation graftablepolymer, and the tertiary amine groups thus chemically bonded to thesurface of the polymer are quaternized with the quatemizing agent.

In other species of this embodiment, an ester containing polymer such asan acrylic polymer, a polyester, a polyesterpolyurethane or a maleicanhydride/methyl vinyl ether copolymer may be subjected to surfacehydrolysis to convert surface ester groups to carboxyl groups which maythen be converted to surface tertiary amine groups through the Curtiusreaction and quaternized with the quatemizing agent.

The heparinizing, step (b), may be practiced in any suitable way and isvery readily practiced simply by immersing the plastic polymer surfacehaving quaternary ammonium groups chemically bonded thereto inalcoholic. sodium heparinate, followed by removal from the surface ofloosely bound heparin which has not complexed with the chemically boundammonium groups, as by numerous distilled water rinses.

The quaternization and the heparinization are readily followed bymeasurement of zeta potential of the treated surface in contact withlactated Ringer's solution. In general, most plastics have a negativezeta potential while the quaternized surfaces give a positive zetapotential. The formation of the heparinized surfaces changes the zetapotential to the negative side and the permanence of the heparinizationcan be followed by changes of zeta potential as the surface is aged incontact with Ringers solution.

Plastic articles of the invention, as compared to the thrombogenicnonheparinized polymers, are substantially nonthrombogenic; recalcifiedhuman blood in contact with the heparinized surfaces remaining unclottedfor up to 20 hours or more, as against only a few minutes for thenonheparinized plastics.

The invention will be most readily understood from a consideration ofthe following specific examples, which, however, are to be considered asillustrative and not restrictive of the invention, the scope of which ismore particularly pointed out in the appended claims.

EXAMPLES EXAMPLE 1 A chloromethylation solution was prepared bydissolving 5 grams of aluminum chloride (AlCl,) and 5 grams ofchloromethyl ether (ClCl-LOCl-h) in ml. of nitrobenzene (C IQNO), andsamples of polystyrene were immersed in such solution at 25 C. for 15seconds. The resulting wet chloromethylated polystyrene samples wereplaced immediately in a 5 percent solution of dimethyl aniline (C,,l-lN(Cl-l in methyl alcohol (Cl'l Ol-l) at 25 C. for 24 hours. Afterwashing free of unreacted reagent by methanol, dilute aqueoushydrochloric acid, and distilled water rinses, in that sequence, thepolystyrene samples having quaternary ammonium groups bonded theretowere immersed in dilute alcoholic sodium heparinate (1 percent by weightof sodium heparinate in 3/1 methanol/water at 25C. for 1 hour.

The samples were repeatedly washed with distilled water until free ofunreacted heparin. These samples were found to have been renderedsubstantially nonthrombogenic; recalcified human blood in contacttherewith remained unclotted for over twenty hours, whereas theuntreated polystyrene clotted it in 9 to l 1 minutes.

The times, temperatures and concentrations of reactants employed in thisexample are noncritical and may be varied substantially, and in lieu ofthe dimethyl aniline other tertiary amines, especially pyridine, may beemployed.

EXAMPLE 2 The procedure of example I was repeated, using samples ofpolycarbonate [C,,ll,-O-COO], in lieu of the polystyrene samples. Thechloromethylation was effected by immersion at 40 C. for 4 hours. Thepolymers after amination, quaternization, and heparinization of thesurface groups also were substantially nonthrombogenic.

EXAMPLE 3 in this example the surfaces of immersible samples ofpolyethylene were radiation grafted with styrene by dipping in thestyrene monomer while subjecting to gamma irradiation of 10 rads, at 25C., for 24 hours. The ungrafted styrene was removed by rinsing withethyl acetate and the polyethylene samples surface grafted withpolystyrene were then subjected to chloromethylation, quatemization andheparinization of the surfaces of the polystyrene grafts as in example1, yielding a polyethylene having heparin chemically bonded to itssurface, which was substantially nonthrombogenic.

Repetitions of this example employing polypropylene, ethylene-propylenerubber, silicone rubber, and tetrafluoroethylene polymer as the polymersurface grafted with styrene which was then chloromethylated, etc., alsoproduced polymers having heparin chemically bonded to their surfaces andrendered substantially nonthrombogenic thereby. By limiting the amountof styrene surfaces grafted to the base polymer, the characteristics ofthe base polymer are substantially retained while rendering the surfacesthereof substantially nonthrombogenic.

EXAMPLE 4 Example l was repeated, employing samples of butadienestyrenecopolymer in lieu of the styrene samples. The chloromethylization waseffected at 70-80 C., and these samples also were rendered substantiallynonthrombogenic.

EXAMPLE 5 Samples of polyvinyl alcohol were immersed in 5 percentchloroacetic anhydride in benzene and refluxed for 24 hours. The sampleswere removed and, while wet, immediately immersed in a l percentsolution of pyridine in methanol and refluxed for 4 hours. After washingfree of unreacted pyridine the quaternized samples were subjected toheparinization as in example 1, and were rendered substantiallynonthrombogenic thereby.

EXAMPLE 6 Samples of polystyrene were radiation grafted with amine byimmersion in a percent solution of 4vinylpyridine in methanol for 24hours, under gamma radiation of reds, and at C. The samples were rinsedwith a solvent for the amine (viz: ethyl acetate) to remove unreactedreagent. The samples then were immersed in a 10 percent solution ofmethyl iodide in methanol and subjected to reflux for 4 hours. Theresulting quaternized material, after washing free of unreacted reagentwas heparinized and washed free of unreacted heparin as in example I.The resulting polymer was substantially nonthrombogenic.

Repetitions of this example, using polyethylene, silicone rubber andtetrafluoroethylene polymer as the polymer subjected to irradiationgrafting with 4-vinylpyridine or 2-vinylpyridine to provide the surfacewith amine grafts for the quaternization with methyl iodide or benzylchloride, followed by the heparinization steps, rendered these basepolymers substantially nonthrombogenic.

While there have been described herein what are at present consideredpreferred embodiments of the invention, it will be clear to thoseskilled in the art that minor variations and changes may be made withoutdeparting from the essence of the invention. It is therefore to beunderstood that the exemplary embodiments are illustrative and notrestrictive of the invention, the scope of which is defined in theappended claims, and that all modifications that come within the rangeof equivalency of the claims are intended to be included therein.

Partial disclosures of the present invention have been published, withthe inventors consent, within the last year preceding the filing of thisapplication and such publications, which include but are not limited toChemical and Engineering News, Vol. 44, No. 15, p. 37, Apr. ll, 1966,and Vol. 44, No. 16, p. 56, Apr. 18, 1966, are incorporated herein byreference and may be referred to for discussion of various aspects andadvantages of the invention.

We claim:

1. A plastic polymer surface rendered substantially nonthrombogenic byheparin chemically combined with quaternary ammonium groups which arechemically bonded to the plastic polymer surface.

2. A plastic polymer surface as defined in claim 1, wherein the plasticpolymer is a synthetic plastic material.

3. A plastic polymer surface as defined in claim I, wherein the plasticpolymer is a flexible polymer.

4. A plastic polymer surface as defined in claim 1, wherein the plasticpolymer is an elastomeric polymer.

5. The process of rendering substantially nonthrombogenic a surface of aplastic polymer article, which comprises the steps of (a) providing saidsurface with quaternary ammonium groups chemically bonded to thepolymer. and (b) heparinizing the quaternary ammonium groups.

6. A process as defined in claim 5 wherein step (b) is effected byimmersing the plastic surface having quaternary ammonium groupschemically bonded thereto in alcoholic sodium heparinate followed byremoval from the surface of loosely bound heparin which has notcomplexed with the chemically bonded ammonium groups.

7. A process as defined in claim 5 wherein in step (a) the polymersurface is provided with the quaternary ammonium groups by chemicaltreatment after formation of the polymer surface.

8. A process as defined in claim 7 wherein in step (a) the polymersurface is provided with the quaternary ammonium groups by (i)chloromethylation followed by (ii) amination with a tertiary amine.

9. A process as defined in claim 8 wherein the tertiary amine is fromthe group consisting of triethyl amine, dimethyl aniline, and pyridine.

10. A process as defined in claim 7 wherein in step (a) the polymersurface is provided with the quaternary ammonium groups by (i) providingthe polymer surface with chloride groups followed by (i) amination witha tertiary amine.

11. A process as defined in claim 7 wherein in step (a) the polymersurface is provided with the quaternary ammonium groups by (i) providingthe surface of the polymer with tertiary amine groups and (ii)quaternizing said tertiary amine groups with the aid of a quaternizingreagent.

[2. A process as defined in claim 1, wherein the quaternizing reagent isselected from the group consisting of methyl iodide and benzyl chloride.

13. A process as defined in claim 11 wherein in step (a) (i) the polymersurface is provided with the tertiary amine groups by radiation graftingof a tertiary amine to the surface of the polymer.

14. A process as defined in claim 11, wherein the polymer beingheparinized is a polymer having carboxyl groups chemically bonded to itssurface, and wherein in step (a) (i) the carboxyl groups are convertedto the tertiary amine groups by the Curtius reaction.

15. A process as defined in claim ll wherein the polymer beingheparinized is a polymer having ester groups chemically polyethylene,tetrafluoroethylene polymer, natural rubber, synthetic elastomer,acrylic polymers, polyesters, polyesterpolyurethanes, and maleicanhydride/methylvinylether copolymers.

2. A plastic polymer surface as defined in claim 1, wherein the plasticpolymer is a synthetic plastic material.
 3. A plastic polymer surface asdefined in claim 1, wherein the plastic polymer is a flexible polymer.4. A plastic polymer surface as defined in claim 1, wherein the plasticpolymer is an elastomeric polymer.
 5. The process of renderingsubstantially nonthrombogenic a surface of a plastic polymer article,which comprises the steps of (a) providing said surface with quaternaryammonium groups chemically bonded to the polymer, and (b) heparinizingthe quaternary ammonium groups.
 6. A process as defined in claim 5wherein step (b) is effected by immersing the plastic surface havingquaternary ammonium groups chemically bonded thereto in alcoholic sodiumheparinate followed by removal from the surface of loosely bound heparinwhich has not complexed with the chemically bonded ammonium groups.
 7. Aprocess as defined in claim 5 wherein in step (a) the polymer surface isprovided with the quaternary ammonium groups by chemical treatment afterformation of the polymer surface.
 8. A process as defined in claim 7wherein in step (a) the polymer surface is provided with the quaternaryammonium groups by (i) chloromethylation followed by (ii) amination witha tertiary amine.
 9. A process as defined in claim 8 wherein thetertiary amine is from the group consisting of triethyl amine, dimethylaNiline, and pyridine.
 10. A process as defined in claim 7 wherein instep (a) the polymer surface is provided with the quaternary ammoniumgroups by (i) providing the polymer surface with chloride groupsfollowed by (i) amination with a tertiary amine.
 11. A process asdefined in claim 7 wherein in step (a) the polymer surface is providedwith the quaternary ammonium groups by (i) providing the surface of thepolymer with tertiary amine groups and (ii) quaternizing said tertiaryamine groups with the aid of a quaternizing reagent.
 12. A process asdefined in claim 1, wherein the quaternizing reagent is selected fromthe group consisting of methyl iodide and benzyl chloride.
 13. A processas defined in claim 11 wherein in step (a) (i) the polymer surface isprovided with the tertiary amine groups by radiation grafting of atertiary amine to the surface of the polymer.
 14. A process as definedin claim 11, wherein the polymer being heparinized is a polymer havingcarboxyl groups chemically bonded to its surface, and wherein in step(a) (i) the carboxyl groups are converted to the tertiary amine groupsby the Curtius reaction.
 15. A process as defined in claim 11 whereinthe polymer being heparinized is a polymer having ester groupschemically bonded to its surface, and wherein in step (a) (i) the estergroups are hydrolyzed to carboxyl groups which are converted to tertiaryamine groups by the Curtius reaction.
 16. A process as defined in claim11, wherein the polymer is selected from the group consisting ofpolystyrene, polyethylene, tetrafluoroethylene polymer, natural rubber,synthetic elastomer, acrylic polymers, polyesters,polyester-polyurethanes, and maleic anhydride/methylvinylethercopolymers.